Proof of principle research shows that the marriage of gene therapy and stem-cell technologies have the potential to allow doctors to correct any genetic diseases that cripple a particular type of cell. So far, Belmonte's approach is applicable only to diseases in which the genetic defect that underlies the disease has been identified. "But there are quite a few of these--and the number will increase," says Mason. Blood disorders are likely to be the first targets for therapy because corrected cells can easily be transferred back to the patient via bone-marrow transplants. Belmonte adds that in the future, the correction of more-complex genetic disorders might become possible, thereby significantly increasing the number of diseases that might be treated with altered iPS cells.
Juan Carlos Izpisúa Belmonte of the Salk Institute in La Jolla, California, and his colleagues in the US and Europe harvested fibroblast cells from the skin of patients with the bone marrow disease Fanconi anaemia, then used standard gene-therapy viruses to replace the defective genes with normal ones.
The researchers then used a second virus to "reset" the cells to their embryonic condition. These induced pluripotent stem cells, or iPS cells, are capable of differentiating into any of the tissues of the body. Indeed, the researchers showed that given the right stimuli, their iPS cells differentiated into disease-free progenitors of bone marrow stem cells.
So far, iPS cells are prone to becoming cancerous, making them too risky for clinical use. However, the research team is working on ways to overcome this obstacle.
If they can, the technique should allow gene therapists to generate limitless supplies of genetically healthy stem cells derived from each individual patient, says Inder Verma, one of the Salk Institute team. With those cells – and the know-how to transform them into whatever tissue is needed – new treatments could emerge for a wide variety of genetic defects, he says.
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"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."
Although hurdles still loom before that theory can become practice—in particular, preventing the reprogrammed cells from inducing tumors—in coming months Belmonte and Verma will be exploring ways to overcome that and other obstacles. In April 2009, they received a $6.6 million from the California Institute Regenerative Medicine (CIRM) to pursue research aimed at translating basic science into clinical cures.
"If we can demonstrate that a combined iPS–gene therapy approach works in humans, then there is no limit to what we can do," says Verma.
Abstract: Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells
The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.
17 pages of supplemental information